Compositions and Methods for Stimulating Collagen Synthesis in the Skin

ABSTRACT

Cosmetic compositions comprising substituted carbamoyl heterocyclic analogs and methods of using such compositions to impart anti-aging benefits to the skin are disclosed. The substituted carbamoyl heterocyclic analogs are believed to have modulatory activity against one or more biochemical pathways implicated in skin aging.

FIELD OF INVENTION

The present invention relates generally to compositions and methods fortopical application to the skin which comprise substituted carbamoylheterocyclic analogs and the use of such compositions to improve theaesthetic appearance of the skin.

BACKGROUND OF THE INVENTION

Collagen is the body's major structural protein and is composed of threeprotein chains wound together in a tight triple helix. This uniquestructure gives collagen a greater tensile strength than steel.Approximately 33 percent of the protein in the body is collagen. Thisprotein supports tissues and organs and connects these structures tobones. In tact, bones are also composed of collagen combined withcertain minerals such as calcium and phosphorus. Collagen plays a keyrole in providing the structural scaffolding surrounding cells thathelps to support cell shape and differentiation, similar to how steelrods reinforce a concrete block. The mesh-like collagen network bindscells together and provides the supportive framework or environment inwhich cells develop and function, and tissues and bones heal.

Collagen is created by fibroblasts, which are specialized skin cellslocated in the dermis. Fibroblasts also produce other skin structuralproteins such as elastin (a protein which gives the skin its ability tosnap back) and glucosaminoglycans (GAGs). GAGs make up the groundsubstance that keeps the dermis hydrated. In order to signal or turn onthe production of skin structural proteins, fibroblast cells havespecially shaped receptors on their outside membranes that act asbinding sites to which signal molecules with a matching shape can fit.When the receptors are bound by the correct combination of signalmolecules (called fibroblast growth factors, or FGFs), the fibroblastbegins the production of collagen. The stimulation of collagen gives theskin its strength, durability, and smooth, plump appearance.

It is therefore an object of the invention to provide new compositionsand methods for stimulating collagen. It is a further object of theinvention to improve the overall appearance of skin, including treating,reversing, and/or preventing signs of aging, such as skin wrinkles, bystimulating collagen, with cosmetic compositions comprising effectiveamounts of substituted carbamoyl heterocyclic analogs.

The foregoing discussion is presented solely to provide a betterunderstanding of nature of the problems confronting the art and shouldnot be construed in any way as an admission as to prior art nor shouldthe citation of any reference herein be construed as an admission thatsuch reference constitutes “prior art” to the instant application.

SUMMARY OF TILE INVENTION

In accordance with the foregoing objectives and others, it hassurprisingly been found that substituted carbamoyl heterocyclic analogsare stimulators of collagen, and thus are beneficial agents againstvarious signs of intrinsic aging and photo-aging of skin.

In one aspect of the invention, a method is provided for improving theaesthetic appearance of human skin comprising topically applying to anarea of the skin in need thereof an effective amount of a substitutedcarbamoyl heterocyclic analog or a cosmetically acceptable salt thereofin a cosmetically acceptable vehicle.

In another aspect of the invention, cosmetic compositions are providedfor improving the aesthetic appearance of skin comprising, in acosmetically acceptable vehicle, an effective amount of a substitutedcarbamoyl heterocyclic analog having the structure of formula I:

where ε₁-ε₃ are independently selected from CR_(a), N, or NR^(b), andwherein the ring A is optionally aromatic or may comprise zero, one, ortwo double bonds;

with the proviso that at least one of ε₁, ε₂, or ε₃ is NR^(b); and inthe case where ε₃ is NR^(b), then ε₂ is a nitrogen atom, and the bondbetween ε₁ and ε₂ is a double bond; in the case where ε₂ is NR^(b), thenε₁ is a nitrogen atom, and the bond between ε₁ and the carbon atom towhich R₁ is attached is a double bond; and in the case where ε₁ isNR^(b), then ε₂ is a nitrogen atom, and the bond between ε₂ and ε₃ is adouble bond;

R^(b) is an aryl group of the form,

R₁ is selected from a group consisting of H, or a C₁₋₂₀ hydrocarbons,independently selected from alkyl, cycloalkyl, haloalkyl, alkoxyalkyl,alkenyl, alkynyl, alkylaryl, heteroalkyl, heteroarylalkyl, arylalkyl,aryl, aminoalkyl, aminoalkylheteroaryl, alkyloxyaryl,alkyloxyheteroaryl, or heteroaryl group optionally substituted with oneor more C₁₋₂₀ alkyl, alkenyl, alkynyl, aryl, or R_(a) groups;

R₂ and R₃ are independently selected from the group consisting of C₁₋₆alkyl, alkenyl, alkynyl, and aryl, which could be optionally connectedto form together with the nitrogen atom to which they are attached a 5,6, or 7 membered ring, saturated or unsaturated, which optionallyfurther comprises one or more heteroatoms in the ring, selected fromoxygen, nitrogen, or sulfur, and wherein R₂ and R₃ are optionallysubstituted with one or more groups R_(a);

R₄-R₈ are independently selected from the group consisting of R_(a),C₁₋₆ alkyl, alkenyl, alkynyl, and aryl, each of which could beoptionally further substituted with one or more groups R_(a);

wherein R_(a) is independently, at each occurrence, selected fromhydrogen, halogen (F, Cl, Br, or I); —OH; —NH₂; —NR^(N)R^(N); —SH; oxo;—CHO; —CO₂H; —O—(C═O)—H; —O—(C═O)—C₁₋₁₀ alkyl; —O—(C═O)—Ar;—(C═O)—O—C₁₋₁₀ alkyl; —(C═O)—O—Ar; —(C═O)—NR^(N)R^(N); —O—C₁₋₁₀ alkyl;—O—Ar; —S—C₁₋₁₀ alkyl; —S—Ar; —Ar; C₁₋₁₀ alkyl; —NR^(N)—CHO;—NR^(N)—(C═O)—C₁₋₁₀ alkyl; —C₁₋₁₀ alkyl—O—C₁₋₁₀ alkyl; perfluoroalkyl;epoxy; azido; thiocyanate; —SO₂—R^(N); or nitro;

wherein R^(N) independently selected, at each occurrence, from hydrogenor a C₁₋₁₆ hydrocarbon radical, optionally substituted with a groupR_(a); and where any two adjacent groups R^(N) may together form a 5, 6,or 7 membered ring;

and wherein any two adjacent R groups can be taken together to form a5-7 member ring, saturated or unsaturated, optionally incorporating O,S, N heteroatoms or substituted with alkyl, haloalkyl, or alkoxy groups;

or a cosmetically acceptable salt thereof.

Also provided is a method of treating one or more signs of skin agingcomprising topically applying to skin in need thereof acollagen-stimulating substituted carbamoyl heterocyclic analog accordingto formula I or a cosmetically acceptable salt thereof.

In another aspect of the invention, a method of treating; reducing,and/or preventing fine lines and/or wrinkles, sagging in human skin,loss of elasticity and molting is provided, comprising topicallyapplying to skin in need thereof, including applying directly to awrinkle or fine line, a composition comprising a collagen-stimulatingsubstituted carbamoyl heterocyclic analog according to formula I or acosmetically acceptable salt thereof.

These and other aspects of the present invention will be betterunderstood by reference to the following detailed description.

DETAILED DESCRIPTION

All terms used herein are intended to have their ordinary meaning unlessotherwise provided. By “cosmetically acceptable” is meant that aparticular component is generally regarding as safe and non-toxic at thelevels employed. The term “prevent,” as used herein, includes delayingthe onset or progression of a particular sign of skin aging. The term“thin skin” includes skin that becomes thinner with chronological agingas well as prematurely thinned skin, which may be caused, for example,by photo-aging. The phrase “individual in need thereof” refers to ahuman that could benefit from improved dermal appearance or health,including males or females. The term “skin” includes, withoutlimitation, the lips, skin of the face, hands, arms, neck, legs, inparticular thighs, and chest. As used herein, the term “consistingessentially of” is intended to limit the invention to the specifiedmaterials or steps and those that do not materially affect the basic andnovel characteristics of the claimed invention, as understood from areading of this specification.

The present invention provides compositions for topical applicationwhich comprise an effective amount of substituted carbamoyl heterocyclicanalogs or a related compound to treat, reverse, ameliorate and/orprevent signs of skin aging. Such signs of skin aging include withoutlimitation, the following:

-   -   (a) treatment, reduction, and/or prevention of fine lines or        wrinkles,    -   (b) reduction of skin pore size,    -   (c) improvement in skin thickness, plumpness, and/or tautness;    -   (d) improvement in skin suppleness and/or softness;    -   (e) improvement in skin tone, radiance, and/or clarity;    -   (f) improvement in procollagen, collagen production, and/or        elastin production;    -   (g) improvement in maintenance and remodeling of collagen and/or        elastin;    -   (h) improvement in skin texture and/or promotion of        retexturization;    -   (i) improvement in skin barrier repair and/or function;    -   (j) improvement in appearance of skin contours;    -   (k) restoration of skin luster and/or brightness;    -   (l) replenishment of essential nutrients and/or constituents in        the skin;    -   (m) decreased by aging and/or menopause;    -   (n) improvement in skin moisturization;    -   (o) increase in skin elasticity and/or resiliency;    -   (p) treatment, reduction, and/or prevention of skin sagging;    -   (q) reduction of pigment spots;    -   (s) improving the appearance of acne scars or marks;    -   (t) improving the appearance of stretch marks; and/or    -   (u) improvement in the appearance of cellulite.

In practice, the compositions of the invention are applied to skin inneed of treatment. That is, skin which suffers from a deficiency or lossin any of the foregoing attributes or which would otherwise benefit fromimprovement in any of the foregoing skin attributes.

In certain preferred embodiments the compositions and methods of theinvention are directed to the prevention, treatment, and/or ameliorationof fine lines and/or wrinkles in the skin. In this case, thecompositions are applied to skin in need of treatment, by which is meantskin having wrinkles and/or fine lines. Preferably, the compositions areapplied directly to the fine lines and/or wrinkles. The compositions andmethods are suitable for treating fine lines and/or wrinkles on anysurface of the skin, including without limitation, the skin of the face,neck, and/or hands.

The cosmetic compositions for treating a skin condition associated withloss of collagen and/or elastin fiber comprise, in a cosmeticallyacceptable vehicle, an amount of a substituted carbamoyl heterocyclicanalogs effective to enhance collagen. These collagenenhancing/stimulating agents may have the structure of formula (I):

where ε₁-ε₃ are independently selected from CR_(a), N, or NR^(b), andwherein the ring A is optionally aromatic or may comprise zero, one, ortwo double bonds;

with the proviso that at least one of ε₁, ε₂, or ε₃ is NR^(b); and inthe case where ε₃ is NR^(b), then ε₂ is a nitrogen atom, and the bondbetween ε₁ and ε₂ is a double bond; in the case where ε₂ is NR^(b), thenε₁ is a nitrogen atom, and the bond between ε₁ and the carbon atom towhich R₁ is attached is a double bond; and in the case where ε₁ isNR^(b), then ε₂ is a nitrogen atom, and the bond between ε₂ and ε₃ is adouble bond;

R^(b) is an aryl group of the form,

R₁ is selected from a group consisting of H, or a C₁₋₂₀ hydrocarbons,independently selected from alkyl, cycloalkyl, haloalkyl, alkoxyalkyl,alkenyl, alkynyl, alkylaryl, heteroalkyl, heteroarylalkyl, arylalkyl,aryl, aminoalkyl, aminoalkylheteroaryl, alkyloxyaryl,alkyloxyheteroaryl, or heteroaryl group optionally substituted with oneor more C₁₋₂₀ alkyl, alkenyl, alkynyl, aryl, or R_(a) groups;

R₂ and R₃ are independently selected from the group consisting of C₁₋₆alkyl, alkenyl, alkynyl, and aryl, which could be optionally connectedto form together with the nitrogen atom to which they are attached a 5,6, or 7 membered ring, saturated or unsaturated, which optionallyfurther comprises one or more heteroatoms in the ring, selected fromoxygen, nitrogen, or sulfur, and wherein R₂ and R₃ are optionallysubstituted with one or more groups R_(a);

R₄-R₃ are independently selected from the group consisting of R_(a),C₁₋₆ alkyl, alkenyl, alkynyl, and aryl, each of which could beoptionally further substituted with one or more groups R_(a);

wherein R_(a) is independently, at each occurrence, selected fromhydrogen, halogen (F, Cl, Br, or I); —OH; —NH₂; —NR^(N)R^(N); —SH; —CN;oxo; —CHO; —CO₂H; —O—(C═O)—H; —O—(C═O)—C₁₋₁₀ alkyl; —O—(C═O)—Ar;—(C═O)—O—C₁₋₁₀ alkyl; —(C═O)—O—Ar; —(C═O)—NR^(N)R^(N); —O—C₁₋₁₀ alkyl;—O—Ar; —S—C₁₋₁₀ alkyl; —S—Ar; —Ar; —C₁₋₁₀ alkyl; —NR^(N)—CHO;—NR^(N)—(C═O)—C₁₋₁₀ alkyl; —C₁₋₁₀ alkyl-O—C₁₋₁₀ alkyl; perfluoroalkyl;epoxy; azido; thiocyanate; —SO₂—R^(N); or nitro;

wherein R^(N) is independently selected, at each occurrence, fromhydrogen or a C₁₋₁₆ hydrocarbon radical, optionally substituted with agroup R_(a); and where any two adjacent groups R^(N) may together form a5, 6, or 7 membered ring;

and wherein any two adjacent R groups can be taken together to form a5-7 member ring, saturated or unsaturated, optionally incorporating O,S, N heteroatoms or substituted with alkyl, haloalkyl, or alkoxy groups;

and wherein any two adjacent R groups can be taken together to form a5-7 member ring, saturated or unsaturated, optionally incorporating O,S, and/or N heteroatoms or substituted with alkyl, haloalkyl, or alkoxygroups;

and wherein any R group may be optionally substituted with one or moresubstituents selected independently at each occurrence from hydrogen;—F; —Cl; —Br; —I; —OH, —OR*; —NH₂; —NHR*; —N(R*)₂; —N(R*)₃ ⁺; —N(R*)—OH;—N(→O)(R*)₂; —O—N(R*)₂; —N(R*)—O—R*; —N(R*)—N(R*)₂; —C═N—R*; —N═C(R*)₂;—C═N—N(R*)₂; —C(═NR*)—N(R*)₂; —SH; —SR*; —CN; —NC; —CHO; —CO₂H; —CO₂ ⁻;—CO₂R*; —(C═O)—S—R*; —O—(C═O)—H; —O—(C═O)—R*; —S—(C═O)—R*; —(C═O)—NH₂;—(C═O)—N(R*)₂; —(C═O)—NHNH₂; —O—(C═O)—NHNH₂; —(C═S)—NH₂; —(C═S)—N(R*)₂;—N(R*)—CHO; —N(R*)—(C═O); —N(R*)—(C═O)—R*; —(C═NR)—O—R*; —O—(C═NR*)—R*,—SCN; —NCS; —NSO; —SSR*; —N(R*)—C(═O)—N(R*)₂; —N(R*)—C(═S)—N(R*)₂;—SO₂—R*; —O—S(═O)₂—R*; —S(═O)₂—OR*; —N(R*)—SO₂—R*; —SO₂—N(R*)₂; —O—SO₃⁻; —O—S(═O)₂OR*; —O—S(═O)—OR*; —O—S(═O)—R*; —S(═O)—OR*; S(═O)—R*; —NO;—NO₂; —NO₃; —O—NO; —O—NO₂; —N₃; —N₂—R*; —N(C₂H₄); —Si(—R*)₃; —CF;—O—CF₃; —(C═O)—R*; —PR*₂; —O—P(═O)(OR*)₂; —P(═O)(OR*)₂; ═O; ═S; ═NR*; analiphatic C₁-C₂₀ hydrocarbon radical; a C₁-C₂₀ aromatic hydrocarbonradical; or a C₁-C₂₀ heteroaryl radical; where R* is independently ateach occurrence hydrogen or a saturated, partially saturated, oraromatic C₁-C₂₀ hydrocarbon radical (preferably a C₁-C₆ hydrocarbon, ora C₁-C₃ hydrocarbon) or halogenated derivative thereof;

or a cosmetically acceptable salt thereof

Any nitrogen atom may be optionally oxidized to the N-oxide or can bequarternized, for example with lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides, and iodides; dialkylsulfites like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides such as benzyl and phenethylbromides, to name a few.

In one embodiment according to formula (I), ε₁ is preferably a nitrogenatom, ε₂ is a group NR^(b) when R^(b) is a substituted aryl ring, andthe collagen-stimulating compound is a substituted carbamoylheterocyclic analog having the structure shown in formula (Ia):

where, R₁, and R₄-R₈, R_(a), and R^(N) are as defined as above;

Q is a 3-7 membered heterocyclic ring, optionally aromatic, and whichmay comprise zero, one, or two double bonds;

X is selected from CR_(a), C(R_(a))₂, N, O, S, NR^(N), or a bond (i.e.absent); and

L₁ and L₂, are independently selected from a bond or a groupX₁-(L₃)_(l)-X₂, where “l” is an integer from 0 to 4; where L₃ isselected from CR_(a), C(R_(a))₂, or a bond; and X₁ and X₂ areindependently selected from N, N^(RN), O, S, or a bond; or acosmetically acceptable salt thereof.

In one embodiment according to formula (Ia), L₁ is —(CH₂)_(m)—, and L₂is —(CH₂)_(n)—, wherein “m” and “n” are independently selected fromintegers from 1-3; and X is selected from N, NR^(N), S, O, or a bond; ora cosmetically acceptable salt thereof.

In another embodiment according to formula (Ia), the Q is a heterocycleselected from the group consisting of aziridine, diaziridine,oxaziridine, azetidine, diazetidine, oxazetidine, pyrrolidine,oxazolidine, thiazolidine, imidazolidine, pyrazolidine, pyrrole,imidazole, pyrazole, 1,3,4-triazole, 1,2,3-triazole, piperidine,morpholine; piperazine; and thiomorpholine, each being optionallysubstituted with one or more groups R_(a), or a cosmetically acceptablesalt thereof.

In a preferred embodiment according to formula (Ia), Q is a heterocycleselected from the group consisting of pyrrolidine, morpholino, andpiperazine, each being optionally substituted with one or more groupsR_(a), or a cosmetically acceptable salt thereof.

In another embodiment according to formula (I), ε₂ is preferably anitrogen atom, ε₃ is a group NR^(b) when R^(b) a substituted aryl ring,and the collagen-stimulating is compound is a substituted carbamoylheterocyclic analog having the structure shown in formula (Ib):

where, R₁, and R₄-R₈, R_(a), and R^(N) are as defined above;

Q is a 3-7 membered heterocyclic ring, optionally aromatic, and whichmay comprise zero, one, or two double bonds;

X is selected from CR_(a), C(R_(a))₂, N, O, S, NR^(N), or a bond (i.e.absent); and

L₁ and L₂ are independently selected from a bond or a groupX₁-(L₃)_(l)-X₂, where “l” is an integer from 0 to 4; where L₃ isselected from CR_(a), C(R_(a))₂, or a bond; and X₁ and X₂ areindependently selected from N, NR^(N), O, S, or a bond; or acosmetically acceptable salt thereof.

In one embodiment according to formula (Ib), L₁ is —(CH₂)_(m)—, and L₂is —(CH₂)_(n)—, wherein “m” and “n” are independently selected fromintegers from 1-3; and X is selected from N, NR^(N), S, O, or a bond; ora cosmetically acceptable salt thereof.

In another embodiment according to formula (Ib), the Q is a heterocycleselected from the group consisting of aziridine, diaziridine,oxaziridine, azetidine, diazetidine, oxazetidine, pyrrolidine,oxazolidine, thiazolidine, imidazolidine, pyrazolidine, pyrrole,imidazole, pyrazole, 1,3,4-triazole, 1,2,3-triazole, piperidine,morpholine, piperazine, and thiomorpholine, each being optionallysubstituted with one or more groups R_(a), or a cosmetically acceptablesalt thereof.

In a preferred embodiment according to formula (Ib), Q is a heterocycleselected from the group consisting of pyrrolidine, morpholino, andpiperazine, each being optionally substituted with one or more groupsR_(a), or a cosmetically acceptable salt thereof.

In another embodiment according to formula (I), ε₁ and ε₂ are preferablynitrogen atoms, ε₃ is a group NR^(b) when R^(b) is a substituted arylring, and the collagen-stimulating compound is a substituted carbamoylheterocyclic analog having the structure shown in formula (Ic):

where, R₁, and R₄-R₈, R_(a), and R^(N) are as defined as above;

Q is a 3-7 membered heterocyclic ring, optionally aromatic, and whichmay comprise zero, one, or two double bonds;

X is selected from CR_(a), C(R_(a))₂, N, O, S, NR^(N), or a bond (i.e.absent); and

L₁ and L₂ are independently selected from a bond or a groupX₁-(L₃)_(l)-X₂, where “l” is an integer from 0 to 4; where L₃ isselected from CR_(a), C(R_(a))₂, or a bond; and X₁ and X₂ areindependently selected from N, NR^(N), O, S, or a bond; or acosmetically acceptable salt thereof.

In one embodiment according to formula (Ic), L₁ is —(CH₂)_(m)—, and L₂is —(CH₂)_(n)—, wherein “m” and “n” are independently selected fromintegers from 1-3; and X is selected from N, NR^(N), S, O, or a bond; ora cosmetically acceptable salt thereof.

In another embodiment according to formula (Ic), the Q is a heterocycleselected from the group consisting of aziridine, diaziridine,oxaziridine, azetidine, diazetidine, oxazetidine, pyrrolidine,oxazolidine, thiazolidine, imidazolidine, pyrazolidine, pyrrole,imidazole, pyrazole, 1,3,4-triazole, 1,2,3-triazole, piperidine,morpholine, piperazine, and thiomorpholine, each being optionallysubstituted with one or more groups R_(a), or a cosmetically acceptablesalt thereof.

In a preferred embodiment according to formula (Ic), Q is a heterocycleselected from the group consisting of pyrrolidine, morpholino, andpiperazine, each being optionally substituted with one or more groupsR_(a), or a cosmetically acceptable salt thereof.

In another embodiment according to formula (I), ε₂ and ε₃ are preferablynitrogen atoms, ε₁ is a group NR^(b) when R^(b) is a substituted arylring, and the collagen-stimulating compound is a substituted carbamoylheterocyclic analog having the structure shown in formula (Id):

where, R₁, and R₄-R₈, R_(a), and R^(N) are as defined as above;

Q is a 3-7 membered heterocyclic ring, optionally aromatic, and whichmay comprise zero, one, or two double bonds;

X is selected from CR_(a), C(R_(a))₂, N, O, S, NR^(N), or a bond (i.e.absent); and

L₁ and L₂ are independently selected from a bond or a groupX₁-(L₃)_(l)-X₂, where “l” is an integer from 0 to 4; where L₃ isselected from CR_(a), C(R_(a))₂, or a bond; and X₁ and X₂ areindependently selected from N, NR^(N), O, S, or a bond; or acosmetically acceptable salt thereof.

In one embodiment according to formula (Id), L₁ is —(CH₂)_(m)—, and L₂is —(CH₂)_(n)—, wherein “m” and “n” are independently selected fromintegers from 1-3; and X is selected from N, NR^(N), S, O, or a bond; ora cosmetically acceptable salt thereof.

In another embodiment according to formula (Id), the Q is a heterocycleselected from the group consisting of aziridine, diaziridine,oxaziridine, azetidine, diazetidine, oxazetidine, pyrrolidine,oxazolidine, thiazolidine, imidazolidine, pyrazolidine, pyrrole,imidazole, pyrazole, 1,3,4-triazole, piperidine, morpholine, piperazine,and thiomorpholine, each being optionally substituted with one or moregroups R_(a), or a cosmetically acceptable salt thereof.

In a preferred embodiment according to formula (Id), Q is a heterocycleselected from the group consisting of pyrrolidine, morpholino, andpiperazine, each being optionally substituted with one or more groupsR_(a), or a cosmetically acceptable salt thereof.

Other illustrative compounds according to the invention are providedbelow.

The invention embraces the use of cosmetically or pharmaceuticallyacceptable (e.g., non-toxic and/or non-irritating) salts. Examples ofthe salts of the compounds in the present invention include salts withalkali metals such as sodium and potassium; salts with alkaline-earthmetals such as calcium and magnesium; salts with amines such asmonoethanolamine; salts with inorganic acids such as hydrochloric acidand sulfuric acid; and salts with organic acids such as citric acid andacetic acid. Special mention may be made of hydrochloride salts.

The cosmetic compositions according to the invention can be formulatedin a variety of forms for topical application and will comprise fromabout 0.0001% to about 1% by weight of one or more compounds accordingto formula (I), and preferably will comprise from about 0.001% to about0.5% by weight, and more preferably from about 0.01% to about 0.2% byweight. The compositions will comprise an effective amount of thesubstituted carbamoyl heterocyclic analog compounds according to formula(I), by which is meant an amount sufficient to enhance collagen and/orstimulate collagen in a given area of skin when topically appliedthereto.

The composition may be formulated in a variety of product forms, suchas, for example, a lotion, cream, serum, spray, aerosol, cake, ointment,essence, gel, paste, patch, pencil, towelette, mask, stick, foam,elixir, concentrate, and the like, particularly for topicaladministration. Preferably the composition is formulated as a lotion,cream, ointment, or gel.

The compositions can include a cosmetically acceptable vehicle. Suchvehicles may take the form of any known in the art suitable forapplication to skin and may include water; vegetable oils; mineral oils;esters such as octal palmitate, isopropyl myristate and isopropylpalmitate; ethers such as dicapryl ether and dimethyl isosorbide;alcohols such as ethanol and isopropanol; fatty alcohols such as cetylalcohol, cetearyl alcohol, stearyl alcohol and biphenyl alcohol;isoparaffins such as isooctane, isododecane and is hexadecane; siliconeoils such as cyclomethicone, dimethicone, dimethicone cross-polymer,polysiloxanes and their derivatives, preferably organomodifiedderivatives; hydrocarbon oils such as mineral oil, petrolatum,isoeicosane and polyisobutene; polyols such as propylene glycol,glycerin, butylene pentylene glycol and hexylene glycol; waxes such asbeeswax and botanical waxes; or any combinations or mixtures of theforegoing.

The vehicle may comprise an aqueous phase, an oil phase, an alcohol, asilicone phase or mixtures thereof. The cosmetically acceptable vehiclemay also comprise an emulsion. Non-limiting examples of suitableemulsions include water-in-oil emulsions, oil-in-water emulsions,silicone-in-water emulsions, water-in-silicone emulsions, wax-in-wateremulsions, water-oil-water triple emulsions or the like having theappearance of a cream, gel or microemulsions. The emulsion may includean emulsifier, such as a nonionic, anionic or amphoteric surfactant.

The oil phase of the emulsion preferably has one or more organiccompounds, including emollients; humectants (such as propylene glycoland glycerin); other water-dispersible or water-soluble componentsincluding thickeners such as veegum or hydroxyalkyl cellulose; gellingagents, such as high MW polyacrylic acid, i.e. CARBOPOL 934; andmixtures thereof. The emulsion may have one or more emulsifiers capableof emulsifying the various components present in the composition.

The compounds suitable for use in the oil phase include withoutlimitation, vegetable oils; esters such as octyl palmitate, isopropylmyristate and isopropyl palmitate; ethers such as dicapryl ether; fattyalcohols such as cetyl alcohol, stearyl alcohol and behenyl alcohol;isoparaffins such as isooctane, isododecane and isohexadecane; siliconeoils such as dimethicones, cyclic silicones, and polysiloxanes;hydrocarbon oils such as mineral oil, petrolatum, isoeicosane andpolyisobutene; natural or synthetic waxes; and the like. Suitablehydrophobic hydrocarbon oils may be saturated or unsaturated, have analiphatic character and be straight or branched chained or containalicyclic or aromatic rings. The oil-containing phase may be composed ofa singular oil or mixtures of different oils.

Hydrocarbon oils include those having 6-20 carbon atoms, more preferably10-16 carbon atoms. Representative hydrocarbons include decane,dodecane, tetradecane, tridecane, and C₈₋₂₀ isoparaffins. Paraffinichydrocarbons are available from Exxon under the ISOPARS trademark, andfrom the Permethyl Corporation. In addition, C₈₋₂₀ paraffinichydrocarbons such as C12 isoparaffin (isododecane) manufactured by thePermethyl Corporation having the tradename Permethyl 99ATM are alsocontemplated to be suitable, Various commercially available C₁₆isoparaffins, such as isohexadecane (having the trademark. Permethyl™)are also suitable. Examples of preferred volatile hydrocarbons includepolydecanes such as isododecane and isodecane, including for example,Permethyl-99A (Presperse Inc.) and the C₇-C₈ through C₁₂-C₁₅isoparaffins such as the Isopar Series available from Exxon Chemicals. Arepresentative hydrocarbon solvent is isododecane.

The oil phase may comprise one or more waxes, including for example,rice bran wax, carnauba wax, ouricurry wax, candelilla wax, montanwaxes, sugar cane waxes, ozokerite, polyethylene waxes, Fischer-Tropschwaxes, beeswax, microcrystalline wax, silicone waxes, fluorinated waxes,and any combination thereof.

Non-limiting emulsifiers included emulsifying waxes, emulsifyingpolyhydric alcohols, polyether polyols, polyethers, mono- or di-ester ofpolyols, ethylene glycol mono-stearates, glycerin mono-stearates,glycerin di-stearates, silicone-containing emulsifiers, soya sterols,fatty alcohols such as cetyl alcohol, fatty acids such as stearic acid,fatty acid salts, and mixtures thereof. The preferred emulsifiersinclude soya sterol, cetyl alcohol stearic acid, emulsifying wax, andmixtures thereof. Other specific emulsifiers that can be used in thecomposition of the present invention include, but are not limited to,one or more of the following: sorbitan esters;polyglyceryl-3-diisostearate; sorbitan monostearate, sorbitantristearate, sorbitan sesquioleate, sorbitan monooleate; glycerol esterssuch as glycerol monostearate and glycerol monooleate; polyoxyethylenephenols such as polyoxyethylene octyl phenol and polyoxyethylene nonylphenol; polyoxyethylene ethers such as polyoxyethylene cetyl ether andpolyoxyethylene stearyl ether; polyoxyethylene glycol esters;polyoxyethylene sorbitan esters; dimethicone copolyols; polyglycerylesters such as polyglyceryl-3-diisostearate; glyceryl laurate;Steareth-2, Steareth-10, and Steareth-20, to name a few. Additionalemulsifiers are provided in the INCI Ingredient Dictionary and Handbook11th Edition 2006, the disclosure of which is hereby incorporated byreference.

These emulsifiers typically will be present in the composition in anamount from about 0.001% to about 10% by weight, in particular in anamount from about 0.01% to about 5% by weight, and more preferably,below 1% by weight.

The oil phase may comprise one or more volatile and/or non-volatilesilicone oils. Volatile silicones include cyclic and linear volatiledimethylsitoxane silicones. In one embodiment, the volatile siliconesmay include cyclodimethicones, including tetramer (D4), pentamer (D5),and hexamer (D6) cyclomethicones, or mixtures thereof. Particularmention may be made of the volatile cyclomethicone-hexamethylcyclotrisiloxane, octamethyl-cyclotetrasiloxane, anddecamethyl-cyclopentasiloxane. Suitable dimethicones are available fromDow Corning under the name Dow Corning 200® Fluid and have viscositiesranging from 0.65 to 600,000 centistokes or higher. Suitable non-polar,volatile liquid silicone oils are disclosed in U.S. Pat. No. 4,781,917,herein incorporated by reference in its entirety. Additional volatilesilicones materials are described in Todd et al., “Volatile SiliconeFluids for Cosmetics”, Cosmetics and Toiletries, 91:27-32 (1976), hereinincorporated by reference in its entirety. Linear volatile siliconesgenerally have a viscosity of less than about 5 centistokes at 25° C.,whereas the cyclic silicones have viscosities of less than about 10centistokes at 25° C. Examples of volatile silicones of varyingviscosities include Dow Corning 200, Dow Corning 244, Dow Corning 245,Dow Corning 344, and Dow Corning 345, (Dow Corning Corp.); SF-1204 andSF-1202 Silicone Fluids (G.E. Silicones), GE 7207 and 7158 (GeneralElectric Co.); and SWS-03314 (SWS Silicones Corp.). Linear, volatilesilicones include low molecular weight polydimethylsiloxane compoundssuch as hexamethyldisiloxane, octamethyltrisiloxane,decamethyltetrasilaxane, and dodecamethylpentasilaxane, to name a few.

Non-volatile silicone oils will typically comprise polyalkylsiloxanes,polyarylsiloxanes, polyalkylarylsiloxanes, or mixtures thereof.Polydimethylsitoxanes are preferred non-volatile silicone oils. Thenon-volatile silicone oils will typically have a viscosity from about 10to about 60,000 centistokes at 25° C., preferably between about 10 andabout 10,000 centistokes, and more preferred still between about 10 andabout 500 centistokes; and a boiling point greater than 250° C. atatmospheric pressure. Non limiting examples include dimethylpolysiloxane (dimethicone), phenyl trimethicone, anddiphenyldimethicone. The volatile and non-volatile silicone oils mayoptionally be substituted will various functional groups such as alkyl,aryl, amine groups, vinyl, hydroxyl, haloalkyl groups, alkylaryl groups,and acrylate groups, to name a few.

The water-in-silicone emulsion may be emulsified with a nonionicsurfactant (emulsifier) such as, for example,polydiorganosiloxane-polyoxyalkylene block copolymers, including thosedescribed in U.S. Pat. No. 4,122,029, the disclosure of which is herebyincorporated by reference. These emulsifiers generally comprise apolydiorganosiloxane backbone, typically polydimethylsitoxane, havingside chains comprising -(EO)m- and/or -(PO)n- groups, where EO isethyleneoxy and PO is 1,2-propyleneoxy, the side chains being typicallycapped or terminated with hydrogen or lower alkyl groups (e.g., C₁₋₆,typically C₁₋₃). Other suitable water-in-silicone emulsifiers aredisclosed in U.S. Pat. No. 6,685,952, the disclosure of which is herebyincorporated by reference herein. Commercially availablewater-in-silicone emulsifiers include those available from Dow Corningunder the trade designations 3225C and 5225C Formulation Aid; SiliconeSF-1528 available from General Electric; ABIL EM 90 and EM 97, availablefrom Goldschmidt Chemical Corporation (Hopewell, Va.); and the SILWETseries of emulsifiers sold by OSI Specialties (Danbury, Conn.).

Examples of water-in-silicone emulsifiers include, but are not limitedto, dimethicone PEG 10/15 crosspolymer, dimethicone copolyol, cetyldimethicone copolyol, PEG-15 lauryl dimethicone crosspolymer,laurylmethicone crosspolymer, cyclomethicone and dimethicone copolyol,dimethicone copolyol (and) caprylic/capric triglycerides, polyglyceryl-4isostearate (and) cetyl dimethicone copolyol (and) hexyl laurate, anddimethicone copolyol (and) cyclopentasiloxane. Preferred examples ofwater-in-silicone emulsifiers include, without limitation, PEG/PPG-18/18dimethicone (trade name 5225C, Dow Corning), PEG/PPG-19/19 dimethicone(trade name BY25-337, Dow Corning), Cetyl PEG/PPG-10/1 dimethicone(trade name Abil EM-90, Goldschmidt Chemical Corporation), PEG-12dimethicone (trade name SF 1288, General Electric), lauryl PEG/PPG-18/18methicone (trade name 5200 FORMULATION AID, Dow Corning), PEG-12dimethicone crosspolymer (trade name 9010 and 9011 silicone elastomerblend, Dow Corning), PEG-10 dimethicone crosspolymer (trade name KSG-20.Shin-Etsu), and dimethicone PEG-10/15 crosspolymer (trade name KSG-210,Shin-Etsu).

The water-in-silicone emulsifiers typically will be present in thecomposition in an amount from about 0.001% to about 10% by weight, inparticular in an amount from about 0.01% to about 5% by weight, and morepreferably, below 1% by weight.

The aqueous phase of the emulsion may include one or more additionalsolvents, including lower alcohols, such as ethanol, isopropanol, andthe like. The volatile solvent may also be a cosmetically acceptableester such as butyl acetate or ethyl acetate; ketones such as acetone orethyl methyl ketone; or the like.

The oil-containing phase will typically comprise from about 10% to about99%, preferably from about 20% to about 85%, and more preferably fromabout 30% to about 70% by weight, based on the total weight of theemulsion, and the aqueous phase will typically comprise from about 1% toabout 90%, preferably from about 5% to about 70%, and more preferablyfrom about 20% to about 60% by weight of the total emulsion. The aqueousphase will typically comprise from about 25% to about 100%, moretypically from about 50% to about 95% by weight water.

The compositions may include liposomes. The liposomes may comprise otheradditives or substances and/or may be modified to more specificallyreach or remain at a site following administration.

The composition may optionally comprise other cosmetic actives andexcipients, obvious to those skilled in the art including, but notlimited to, fillers, emulsifying agents, antioxidants, surfactants, filmformers, chelating agents, gelling agents, thickeners, emollients,humectants, moisturizers, vitamins, minerals, viscosity and/or rheologymodifiers, sunscreens, keratolytics, depigmenting agents, retinoids,hormonal compounds, alpha-hydroxy acids, alpha-keto acids,anti-mycobacterial agents, antifungal agents, antimicrobials,antivirals, analgesics, lipidic compounds, anti-allergenic agents, H1 orH2 antihistamines, anti-inflammatory agents, anti-irritants,antineoplastics, immune system boosting agents, immune systemsuppressing agents, anti-acne agents, anesthetics, antiseptics, insectrepellents, skin cooling compounds, skin protectants, skin penetrationenhancers, exfollients, lubricants, fragrances, colorants, depigmentingagents, hypopigmenting agents, preservatives, stabilizers,pharmaceutical agents, photostabilizing agents, sunscreens, and mixturesthereof. In addition to the foregoing, the cosmetic compositions of theinvention may contain any other compound for the treatment of skindisorders.

Colorants may include, for example, organic and inorganic pigments andpearlescent agents. Suitable inorganic pigments include, but are notlimited to, titanium oxide, zirconium oxide and cerium oxide, as well aszinc oxide, iron oxide, chromium oxide and ferric blue. Suitable organicpigments include barium, strontium, calcium, and aluminium lakes andcarbon black. Suitable pearlescent agents include mica coated withtitanium oxide, with iron oxide, or with natural pigment.

Various fillers and additional components may be added. Fillers arenormally present in an amount of about 0 weight % to about 20 weight %,based on the total weight of the composition, preferably about 0.1weight % to about 10 weight %. Suitable fillers include withoutlimitation silica, treated silica, talc, zinc stearate, mica, kaolin,Nylon powders such as Orgasol™, polyethylene powder, Teflon™, starch,boron nitride, copolymer microspheres such as Expancel™ (NobelIndustries), Polytrap™ (Dow Corning) and silicone resin microbeads(Tospearl™ from Toshiba), and the like.

In one embodiment of the invention, the compositions may includeadditional skin actives such as, but are not limited to, botanicals,keratolytic agents, desquamating agents, keratinocyte proliferationenhancers, collagenase inhibitors, elastase inhibitors, depigmentingagents, anti-inflammatory agents, steroids, anti-acne agents,antioxidants, salicylic acid or salicylates, thiodipropionic acid oresters thereof, and advanced glycation end-product (AGE) inhibitors.

In a specific embodiment, the composition may comprise at least oneadditional botanical, such as, for example, a botanical extract, anessential oil, or the plant itself. Suitable botanicals include, withoutlimitation, extracts from Abies pindrow, Acacia catechu, Anogeissuslatifolia, Asmunda japonica, Azadirachta indica, Butea frondosa, Buteamonosperma, Cedrus deodara, Entblica officinalis, Ficus benghalensis,Glycyrrhiza glabra, Ilex purpurea Hassk, Inniula racemosa, Ligusticumchiangxiong, Ligusticum lucidum, Mallotus philippinensis, Mimusopselengi, Morinda citrifolia, Moringa oleifera, Naringi crenulata, Neriumindicum, Psoralea corylifolia, Stenoloma chusana, Terminalia bellerica,tomato glycolipid, Sapindus rarak, Humulus japonicus, Eclipta prostrate,Amorphophallus campanulatus, Sesbania grandiflora, Pouzolzia pentandra,Melicope hayesii, Ixora chinensis, Erythina indica, Medemia noblis,Tiliacora triandra, Derris scandens, Portulaca oleracea, Alismaorientale, and mixtures thereof.

The composition may comprise additional active ingredients havinganti-aging benefits, as it is contemplated that synergistic improvementsmay be obtained with such combinations. Exemplary anti-aging componentsinclude, without limitation, botanicals (e.g., Butea Frondosa extract);thiodipropionic acid (TDPA) and esters thereof; retinoids (e.g.,all-trans retinoic acid, 9-cis retinoic acid, phytanic acid and others);hydroxy acids (including alpha-hydroxyacids and beta-hydroxyacids),salicylic acid and salicylates; exfoliating agents (e.g., glycolic acid,3,6,9-trioxaundecanedioic acid, etc.), estrogen synthetase stimulatingcompounds (e.g., caffeine and derivatives); compounds capable ofinhibiting 5 alpha-reductase activity (e.g., linolenic acid, linoleicacid, finasteride, and mixtures thereof); barrier function enhancingagents (e.g., ceramides, glycerides, cholesterol and its esters,alpha-hydroxy and omega-hydroxy fatty acids and esters thereof, etc.);collagenase inhibitors; and elastase inhibitors; to name a few. Furtheradditional actives useful for topical application to skin includeperilla oil, mangostine, palmitoyl lysytaminovaleroyl lysine (palmitoylK-ava-K), palmatoyl tetrapeptide-10 (KTFK), L-4-thiazolylatanine,cis-6-nonenol, desthiobiotin,N-(4-mesyloxybenzyl)-N-methoxyethyl-4-chlorobenzene carboxamide,N-(4-mesyloxybenzyl)-N-isobutyl benzenesulfonamide, retinyl oleate,carvacrol, and mixtures thereof.

Exemplary retinoids include, without limitation, retinoic acid (e.g.,all-trans or 13-cis) and derivatives thereof, retinol (Vitamin A) andesters thereof, such as retinol palmitate, retinol acetate and retinolpropionate, and salts thereof.

In another embodiment, the topical compositions of the present inventionmay also include one or more of the following: a skin penetrationenhancer, an emollient, a skin plumper, an optical diffuser, asunscreen, an exfoliating agent, and an antioxidant.

An emollient provides the functional benefits of enhancing skinsmoothness and reducing the appearance of fine lines and coarse wrinklesExamples include isopropyl myristate, petrolatum, isopropyl lanolate,silicones (e.g., methicone, dimethicone), oils, mineral oils, fatty acidesters, or any mixtures thereof. The emollient may be preferably presentfrom about 0.1 wt % to about 50 wt % of the total weight of thecomposition.

A skin plumper serves as a collagen enhancer to the skin. An example ofa suitable, and preferred, skin plumper is palmitoyl oligopeptide. Otherskin plumpers are collagen and/or other glycosaminoglycan (GAG)enhancing agents. When present, the skin plumper may comprise from about0.1 wt % to about 20 wt % of the total weight of the composition.

An optical diffuser is a particle that changes the surface optometricsof skin, resulting in a visual blurring and softening of, for example,lines and wrinkles. Examples of optical diffusers that can be used inthe present invention include, but are not limited to, boron nitride,mica, nylon, polymethylmethacrylate (PMMA), polyurethane powder,sericite, silica, silicone powder, talc, Teflon, titanium dioxide, zincoxide, or any mixtures thereof. When present, the optical diffuser maybe present from about 0.01 wt % to about 20 wt % of the total weight ofthe composition.

A sunscreen for protecting the skin from damaging ultraviolet rays mayalso be included. Preferred sunscreens are those with a broad range ofUVB and UVA protection, such as octocrylene, avobenzone (Parsol 1789),octyl methoxycinnamate, octyl salicylate, oxybenzone, homosylate,benzophenone, camphor derivatives, zinc oxide, and titanium dioxide,When present, the sunscreen may comprise from about 0.01 wt % to about70 wt % of the composition.

Suitable exfoliating agents include, for example, alpha-hydroxyacids,beta-hydroxyacids, oxaacids, oxadiacids, and their derivatives such asesters, anhydrides and salts thereof. Suitable hydroxy acids include,for example, glycolic acid, lactic acid, malic acid, tartaric acid,citric acid, 2-hydroxyalkanoic acid, mandelic acid, salicylic acid andderivatives thereof. A preferred exfoliating agent is glycolic acid.When present, the exfoliating agent may comprise from about 0.1 wt % toabout 80 wt % of the composition.

An antioxidant functions, among other things, to scavenge free radicalsfrom skin to protect the skin from environmental aggressors. Examples ofantioxidants that may be used in the present compositions includecompounds having phenolic hydroxy functions, such as ascorbic acid andits derivatives/esters; beta-carotene; catechins; curcumin; ferulic acidderivatives (e.g. ethyl ferulate, sodium ferulate); gallic acidderivatives (e.g., propyl gallate); lycopene; reductic acid; rosmarinicacid; tannic acid; tetrahydrocurcumin; tocopherol and its derivatives;uric acid; or any mixtures thereof. Other suitable antioxidants arethose that have one or more thiol functions (—SH), in either reduced ornon-reduced form, such as glutathione, lipoic acid, thioglycolic acid,and other sulfhydryl compounds. The antioxidant may be inorganic, suchas bisulfites, metabisulfites, sulfites, or other inorganic salts andacids containing sulfur. Compositions of the present invention maycomprise an antioxidant preferably from about 0.001 wt % to about 10 wt%, and more preferably from about 0.01 wt % to about 5 wt %, of thetotal weight of the composition.

Other conventional additives include: vitamins, such as tocopherol andascorbic acid; vitamin derivatives such as ascorbyl monopalmitate;thickeners such as hydroxyalkyl cellulose; gelling agents; structuringagents such as bentonite, smectite, magnesium aluminum silicate andlithium magnesium silicate; metal chelating agents such as EDTA;pigments such as zinc oxide and titanium dioxide; colorants; emollients;and humectants.

It is preferred that the composition be essentially free of componentshaving a strong oxidizing potential, including for example, organic orinorganic peroxides. By “essentially free of” these components is meantthat the amounts present are insufficient to have a measurable impact onthe collagen I, desmogleins, and/or dermatopontin enhancing activity ofthe substituted carbamoyl heterocyclic analog. In some embodiments, thiswill be, on a molar basis in relation to the amount of substitutedcarbamoyl heterocyclic analog, less than 1%.

In one embodiment, the composition of the invention comprising asubstituted carbamoyl heterocyclic analog may have a pH between about 1and about 8. In certain embodiments, the pH of the composition will beacidic, i.e., less than 7.0, and preferably will be between about 2 andabout 7, more preferably between about 3.5 and about 5.5.

The invention provides a method for treating aging skin by topicallyapplying a composition comprising a substituted carbamoyl heterocyclicanalog, preferably in a cosmetically acceptable vehicle, over theaffected area for a period of time sufficient to reduce, ameliorate,reverse or prevent dermatological signs of aging. This method isparticularly useful for treating signs of skin photoaging and intrinsicaging.

Generally, the improvement in the condition and/or aesthetic appearanceis selected from the group consisting of: reducing dermatological signsof chronological aging, photo-aging, hormonal aging, and/or actinicaging; preventing and/or reducing the appearance of lines and/orwrinkles; reducing the noticeability of facial lines and wrinkles,facial wrinkles on the cheeks, forehead, perpendicular wrinkles betweenthe eyes, horizontal wrinkles above the eyes, and around the mouth,marionette lines, and particularly deep wrinkles or creases; preventing,reducing, and/or diminishing the appearance and/or depth of lines and/orwrinkles; improving the appearance of suborbital lines and/orperiorbital lines; reducing the appearance of crow's feet; rejuvenatingand/or revitalizing skin, particularly aging skin; reducing skinfragility; preventing and/or reversing of loss of glycosaminoglycansand/or collagen, in particular collagen I; ameliorating the effects ofestrogen imbalance; preventing skin atrophy; preventing, reducing,and/or treating hyperpigmentation; minimizing skin discoloration;improving skin tone, radiance, clarity and/or tautness; preventing,reducing, and/or ameliorating, skin sagging; improving skin firmness,plumpness, suppleness and/or softness; improving procollagen and/orcollagen production; improving skin texture and/or promotingretexturization; improving skin barrier repair and/or function;improving the appearance of skin contours; restoring skin luster and/orbrightness; minimizing dermatological signs of fatigue and/or stress;resisting environmental stress; replenishing ingredients in the skindecreased by aging and/or menopause; improving communication among skincells; increasing cell proliferation and/or multiplication; increasingskin cell metabolism decreased by aging and/or menopause; retardingcellular aging; improving skin moisturization; enhancing skin thickness;increasing skin elasticity and/or resiliency; enhancing exfoliation;improving microcirculation; decreasing and/or preventing celluliteformation; and any combinations thereof.

Without wishing to be bound by any particular theory, it is believedthat the compositions of the present invention enhance and improve theaesthetic appearance of skin by stimulation of collagen.

The composition will typically be applied to the skin one, two, or threetimes daily for as long as is necessary to achieve desired anti-agingresults. The treatment regiment may comprise daily application for atleast one week, at least two weeks, at least four weeks, at least eightweeks, or at least twelve weeks. Chronic treatment regimens are alsocontemplated.

The substituted carbamoyl heterocyclic analog active component istopically applied to an “individual in need thereof,” by which is meantan individual that stands to benefits from reducing visible signs ofskin damage or aging. In a specific embodiment, the substitutedcarbamoyl heterocyclic analog component is provided in apharmaceutically, physiologically, cosmetically, anddermatologically-acceptable vehicle, diluent, or carrier, where thecomposition is topically applied to an affected area of skin and left toremain on the affected area in an amount effective for improving thecondition and aesthetic appearance of skin.

In one embodiment, methods for treating fine lines and wrinkles comprisetopically applying the inventive substituted carbamoyl heterocyclicanalog compositions to the skin of an individual in need thereof, e.g.,topically application directly to the fine line and/or wrinkle in anamount and for a time sufficient to reduce the severity of the finelines and/or wrinkles or to prevent or inhibit the formation of new finelines and/or wrinkles. The effect of a composition on the formation orappearance of fine lines and wrinkles can be evaluated qualitatively,e.g., by visual inspection, or quantitatively, e.g., by microscopic orcomputer assisted measurements of wrinkle morphology (e.g., the number,depth, length, area, volume and/or width of wrinkles per unit area ofskin). This embodiment includes treatment of wrinkles on the skin of thehands, arms, legs, neck, chest, and face, including the forehead,

It is also contemplated that the compositions of the invention will beuseful for treating thin skin by topically applying the composition tothin skin of an individual in need thereof. “Thin skin” is intended toinclude skin that is thinned due to chronological aging, menopause, orphoto-damage. In some embodiments, the treatment is for thin skin inmen, whereas other embodiments treat thin skin in women, pre-menopausalor post-menopausal, as it is believed that skin thins differently withage in men and women, and in particular in women at different stages oflife.

The method of the invention may be employed prophylactically toforestall aging including in patients that have not manifested signs ofskin aging, most commonly in individuals under 25 years of age. Themethod may also reverse or treat signs of aging once manifested as iscommon in patients over 25 years of age.

The following examples are meant to demonstrate certain aspects of theinvention in a non-limiting fashion.

EXAMPLES Example 1

The compounds 1-5, and 8-9 were assayed for stimulation of collagensynthesis as follows. Human dermal fibroblasts (Cascade Biologics,Portland, Oreg.) were plated at 10,000 cells/well in 96-well cultureplates in supplemented medium (DMEM, 10% Fetal Bovine Serum, 1%Penicillin/Streptomycin and 1% L-Glutamine) overnight in humidifiedatmosphere of 10% CO₂ at 37° C. The next day, the medium was replacedwith fresh medium (DMEM, 1% Penicillin/Streptomycin and 1% L-Glutamine)and the compounds dissolved DMSO were added to the wells in triplicateat a concentration of 0.0005%, DMSO solution was used a control.Following 48-hour incubation, the plates were removed from the incubatorand the medium from each well was collected for the procollagen assay.

Collagen production was measured using procollagen type I C-peptide(PIP) EIA kit (Takara Bio, Inc., Japan). Briefly, the conditioned mediumwas diluted 1:10 in Sample Diluent, 20 μl of diluted conditioned mediumand 100 μl of antibody-POD conjugate solution were added to the wells ofthe Takara HASA plate. The ELISA plate was incubated at 37° C. for 3hours before the wells were washed four times with 400 μl of 1×PBS. Atthe end of wash, 100 μl of substrate solution (supplied with kit) wasadded to the wells and incubated at room temperature for 15 minutes. Thereaction was stopped by adding 100 μl of 1N sulfuric acid to the wells.The absorbance was measured on a spectrophotometer at 450 nm wavelength.The amount of procollagen peptide in the conditioned medium wascalculated from the standard curve. The stimulation of collagenproduction was shown as an increase in collagen over the control.

For compounds 1-5 the results were:

TABLE 1 Compound R^(b) R_(a) R₁

% Collagen Stimulation 1

H

73.2% 2

23.1% 3

H

13.5% 4

H

12.5% 5

H

45.23% 

For compounds 8-9 the results were:

TABLE 2 Compound R^(b) R_(a) R₁

% Collagen Stimulation 8

H

83.7% 9

H

62.2%

Results illustrate that the compounds included in Tables 1 and 2 arecollagen stimulators, and that compounds 1, 8 and 9 are potentstimulators of collagen synthesis.

Example 2

Other illustrative examples are shown below in Tables 3 and 4.

TABLE 3 Compound R^(b) R_(a) R₁

6

H

7

TABLE 4 Compound R^(b) R_(a) R₁

10

H

11

H

12

H

13

H

Example 3 Illustrative Compositions

The cosmetic compositions set forth in Table 5 are illustrative of theinvention and are useful for topical application to the skin to enhanceits aesthetic appearance.

TABLE 5 Composition 1 2 3 4 5 Components Weight % Compound 1 of Table 10.01 0.05 — — — Compound 5 of Table 1 — — 0.1 — — Compound 8 of Table 2— — — 0.05 — Compound 9 of Table 2 0.05 Acrylates/C10-30 Alkyl 1 1 1 1 1Acrylate Crosspolymer Cetyl Ethylhexanoate 10 10 10 10 10 C12-15 AlkylBenzoate 3.9 3.9 3.9 3.9 3.9 Isopropyl Isostearate 3 3 3 3 3 Diisopropyldimer 0.1 0.1 0.1 0.1 0.1 dillinoleate Tocopheryl acetate 0.5 0.5 0.50.5 0.5 Butylene glycol 2 2 2 2 2 Propylene glycol 1 1 1 1 1 DimethiconePEG-7 0.5 0.5 0.5 0.5 0.5 isostearate Methyl gluceth-20 0.5 0.5 0.5 0.50.5 Triethanolamine 1 1 1 1 1 Acrylates/acrylamide 1.5 1.5 1.5 1.5 1.5copolymer/mineral oil DMDM Hydantoin/ 0.4 0.4 0.4 0.4 0.4Iodopropynylbutylcarbonate Deionized water q.s. q.s. q.s. q.s. q.s.Total: 100 100 100 100 100

All references including patent applications and publications citedherein are incorporated herein by reference in their entirety and forall purposes to the same extent as if each individual publication orpatent or patent application was specifically and individually indicatedto be incorporated by reference in its entirety for all purposes. Manymodifications and variations of this invention can be made withoutdeparting from its spirit and scope, as will be apparent to thoseskilled in the art. The specific embodiments described herein areoffered by way of example only, and the invention is to be limited onlyby the terms of the appended claims, along with the full scope ofequivalents to which such claims are entitled.

1. A method for improving the aesthetic appearance of human skincomprising topically applying to an area of the skin in need thereof, ina cosmetically acceptable vehicle, an effective amount of acollagen-stimulating compound of formula I:

where: ε₁-ε₃ are independently selected from CR_(a), N, or NR^(b), andwherein the ring A is optionally aromatic or may comprise zero, one, ortwo double bonds; with the proviso that at least one of ε₁, ε₂, or ε₃ isNR^(b); and in the case where ε₃ is NR^(b), then ε₂ is a nitrogen atom,and the bond between ε₁ and ε₂ is a double bond; in the case where ε₂ isNR^(b), then ε₁ is a nitrogen atom, and the bond between ε₁ and thecarbon atom to which R₁ is attached is a double bond; and in the casewhere ε₁ is NR^(b), then ε₂ is a nitrogen atom, and the bond between ε₂and ε₃ is a double bond; R^(b) is an aryl group of the form,

R₁ is selected from a group consisting of H, or a C₁₋₆ alkyl, alkenyl,alkynyl, aryl, or heteroaryl group optionally substituted with one ormore C₁₋₆ alkyl, alkenyl, alkynyl, aryl, or R_(a) groups; R₂ and R₃ areindependently selected from the group consisting of C₁₋₆ alkyl, alkenyl,alkynyl, and aryl, which could be optionally connected to form togetherwith the nitrogen atom to which they are attached a 5, 6, or 7 memberedring, saturated or unsaturated, which optionally further comprises oneor more heteroatoms in the ring, selected from oxygen, nitrogen, orsulfur, and wherein R₂ and R₃ are optionally substituted with one ormore groups R_(a); R₄-R₈ are independently selected from the groupconsisting of R_(a), C₁₋₆ alkyl, alkenyl, alkynyl, and aryl, each ofwhich could be optionally further substituted with one or more groupsR_(a); wherein R_(a) is independently, at each occurrence, selected fromhydrogen, halogen (F, Cl, Br, or I); —OH; —NH₂; —NR^(N)R^(N); —SH; —CN;oxo; —CHO; —CO₂H; —O—(C═O)—H; —O—(C═O)—C₁₋₁₀ alkyl; —O—(C═O)—Ar;—(C═O)—O—C₁₋₁₀ alkyl; —(C═O)—O—Ar; —(C═O)—NR^(N)R^(N); —O—C₁₋₁₀ alkyl;—O—Ar; —S—C₁₋₁₀ alkyl; —S—Ar; —Ar; —C₁₋₁₀ alkyl; —NR^(N)—CHO;—NR^(N)—(C═O)—C₁₋₁₀ alkyl; —C₁₋₁₀ alkyl-O—C₁₋₁₀ alkyl; perfluoroalkyl;epoxy; azido; thiocyanate; —SO₂—R^(N); or nitro; wherein R^(N) isindependently selected, at each occurrence, from hydrogen or a C₁₋₁₆hydrocarbon radical, optionally substituted with a group R_(a); andwhere any two adjacent groups R^(N) may together form a 5, 6, or 7membered ring; or a cosmetically acceptable salt thereof.
 2. The methodaccording to claim 1, wherein said compound of structure I is selectedfrom the group of compounds consisting of:

and mixtures thereof, where R₁, R₄-R₈, R_(a), and R^(N) are as definedin claim 1; and Q is a 3-7 membered heterocyclic ring, optionallyaromatic, and which may comprise zero, one, or two double bonds; X isselected from CR_(a), C(R_(a))₂, N, O, S, NR^(N), or a bond (i.e.,absent); and L₁ and L₂, are independently selected from a bond or agroup X₁-(L₃)_(l)-X₂, where “l” is an integer from 0 to 4; where L isselected front CR_(a), C(R_(a))₂, or a bond; and X₁ and X₂ areindependently selected from N, —NR^(N), O, S, or a bond; or acosmetically acceptable salt thereof.
 3. The method according to claim2, wherein L₁ is —(CH₂)_(m)—, and L₂ is —(CH₂)_(n)—, wherein “m” and “n”are independently selected from integers from 1-3; and X is selectedfrom N, NR^(N), S, O, or a bond; or a cosmetically acceptable saltthereof.
 4. The method according to claim 3, wherein ring Q is aheterocycle selected from the group consisting of aziridine,diaziridine, oxaziridine, azetidine, diazetidine, oxazetidine,pyrrolidine, oxazolidine, thiazolidine, imidazolidine, pyrazolidine,pyrrole, imidazole, pyrazole, 1,3,4-triazole, 1,2,3-triazole,piperidine, morpholine, piperazine, and thiomorpholine, each beingoptionally substituted with one or more groups R_(a).
 5. The methodaccording to claim 4, wherein ring Q is a heterocycle selected from thegroup consisting of pyrrolidine, morpholine, and piperazine, each beingoptionally substituted with one or more groups R_(a).
 6. The methodaccording to claim 5, wherein R₄ to R₈ are independently hydrogen,methyl, ethyl, propyl, chloro, or bromo, with at least two of R₄ to R₈being hydrogen.
 7. The method according to claim 6, wherein saidcompound has the structure I_(a).
 8. The method according to claim 7,wherein the heterocycle is pyrrolidine.
 9. The method according to claim8, wherein R_(a) is hydrogen, methyl, ethyl, propyl, and R₁ is hydrogen,methyl, ethyl, or propyl.
 10. The method according to claim 1, whereinthe compound has the structure:

and wherein R^(b), R_(a), R₁, and Q are as set forth below: R^(b) R_(a)R₁

H

H

H

H


11. The method according to claim 7, wherein the heterocycle ismorpholine.
 12. The method according to claim 11, wherein R_(a) ishydrogen, methyl, ethyl, propyl, and R₁ is hydrogen, methyl, ethyl, orpropyl.
 13. The method according to claim 7, wherein the heterocycle ispiperazine.
 14. The method according to claim 13, wherein R_(a) ishydrogen, methyl, ethyl, propyl, and R₁ is hydrogen, methyl, ethyl, orpropyl.
 15. The method according to claim 1, wherein the compound hasthe structure:

and wherein R^(b), R_(a), R₁, and Q are as set forth below: R^(b) R_(a)R₁

H

H


16. The method according to claim 1, wherein said aesthetic improvementof said skin is selected from the group consisting of: (a) treatment,reduction, and/or prevention of fine lines or wrinkles, (b) reduction ofskin pore size, (c) improvement in skin thickness, plumpness, and/ortautness; (d) improvement in skin suppleness and/or softness; (e)improvement in skin tone, radiance, and/or clarity; (f) improvement inprocollagen, collagen, and/or elastin production; (g) improvement inmaintenance and remodeling of collagen and/or elastin; (h) improvementin skin texture and/or promotion of retexturization; (i) improvement inskin barrier repair and/or function; (j) improvement in appearance ofskin contours; (k) restoration of skin luster and/or brightness; (l)replenishment of essential nutrients and/or constituents in the skin;(m) improvement of skin appearance decreased by menopause; (n)improvement in skin moisturization; (o) increase in skin elasticityand/or resiliency; (p) treatment, reduction, and/or prevention of skinsagging; (q) reduction of pigment spots; (s) improving the appearance ofacne scars or marks; (t) improving the appearance of stretch marks;and/or (u) improvement in the appearance of cellulite.
 17. The methodaccording to claim 16, wherein said aesthetic improvement of said skinis the treatment, reduction, and/or prevention of: fine lines and/orwrinkles, skin sagging, or loss of elasticity.
 18. The method accordingto claim 17, wherein said aesthetic improvement of said skin is thetreatment of wrinkles and/or fine lines on the skin, and wherein saidmethod comprises topically applying an effective amount of acollagen-stimulating compound of formula I or a cosmetically acceptablesalt thereof in a cosmetically acceptable vehicle to affected skin of anindividual in need thereof, for a time sufficient to reduce the severityof said wrinkles or fine lines.
 19. The method according to claim 18,wherein said collagen-stimulating compound of formula I or acosmetically acceptable salt thereof is applied to said skin at leastonce daily for a period of at least four weeks.
 20. A cosmeticcomposition for improving the aesthetic appearance of human skincomprising a cosmetically acceptable vehicle in the form of awater-in-oil or oil-in-water emulsion, and an effective amount of acollagen-stimulating compound of formula I:

where: ε₁-ε₃ are independently selected from CR_(a), N, or NR^(b), andwherein the ring A is optionally aromatic or may comprise zero, one, ortwo double bonds; with the proviso that at least one of ε₁, ε₂, or ε₃ isNR^(b); and in the case where ε₃ is NR^(b), then ε₂ is a nitrogen atom,and the bond between ε₁ and ε₂ is a double bond; in the case where ε₂ isNR^(b), then ε₁ is a nitrogen atom, and the bond between ε₁ and thecarbon atom to which R₁ is attached is a double bond; and in the casewhere ε₁ is NR^(b), then ε₂ is a nitrogen atom, and the bond between ε₂and ε₃ is a double bond; R^(b) is an aryl group of the form,

R₁ is selected from a group consisting of H, or a C₁₋₆ alkyl, alkenyl,alkynyl, aryl, or heteroaryl group optionally substituted with one ormore C₁₋₆ alkyl, alkenyl, alkynyl, aryl, or R_(a) groups; R₂ and R₃ areindependently selected from the group consisting of C₁₋₆ alkyl, alkenyl,alkynyl, and aryl, which could be optionally connected to form togetherwith the nitrogen atom to which they are attached a 5, 6, or 7 memberedring, saturated or unsaturated, which optionally further comprises oneor more heteroatoms in the ring, selected from oxygen, nitrogen, orsulfur, and wherein R₂ and R₃ are optionally substituted with one ormore groups R_(a); R₄-R₈ are independently selected from the groupconsisting of R_(a), C₁₋₆ alkyl, alkenyl, alkynyl, and aryl, each ofwhich could be optionally further substituted with one or more groupsR_(a); wherein R_(a) is independently, at each occurrence, selected fromhydrogen, halogen (F, Cl, Br, or I); —OH; —NH₂; —NR^(N)R^(N); —SH, —CN;oxo; —CHO; —CO₂H; —O—(C═O)—H; —O—(C═O)—C₁₋₁₀ alkyl; —O—(C═O)—Ar;—(C═O)—O—C₁₋₁₀ alkyl; —(C═O)—O—Ar; —(C═O)—NR^(N)R^(N); —O—C₁₋₁₀ alkyl;—O—Ar; —S—C₁₋₁₀ alkyl; —S—Ar; —Ar; —C₁₋₁₀ alkyl; —NR^(N)—CHO;—NR^(N)—(C═O)—C₁₋₁₀ alkyl; —C₁₋₁₀ alkyl-O—C₁₋₁₀ alkyl; perfluoroalkyl;epoxy; azido; thiocyanate; —SO₂—R^(N); or nitro; wherein R^(N) isindependently selected, at each occurrence, from hydrogen or a C₁₋₁₆hydrocarbon radical, optionally substituted with a group R_(a); andwhere any two adjacent groups R^(N) may together form a 5, 6, or 7membered ring; or a cosmetically acceptable salt thereof.
 21. Thecosmetic composition to claim 20, wherein said compound of structure (I)is selected from the group of compounds consisting of:

and mixtures thereof, where R₁, R₄-R₈, R_(a), and R^(N) are as definedin claim 22; and Q is a 3-7 membered heterocyclic ring, optionallyaromatic, and which may comprise zero, one, or two double bonds; X isselected from CR_(a), C(R_(a))₂, N, O, S, NR^(N), or a bond (i.e.,absent); and L₁ and L₂ are independently selected from a bond or a groupX₁-(L₃)_(l)-X₂, where “l” is an integer from 0 to 4; where L₃ isselected from CR_(a), C(R_(a))₂, or a bond; and X₁ and X₂ areindependently selected from N, NR^(N), O, S, or a bond; or acosmetically acceptable salt thereof.
 22. The cosmetic compositionaccording to claim 21, wherein L₁ is —(CH₂)_(m)—, and L₂ is —(CH₂)_(n)—,wherein “m” and “n” are independently selected from integers from 1-3;and X is selected from N, NR^(N), S, O, or a bond; or a cosmeticallyacceptable salt thereof.
 23. The cosmetic composition according to claim22, wherein ring Q is a heterocycle selected from the group consistingof aziridine, diaziridine, oxaziridine, azetidine, diazetidine,oxazetidine, pyrrolidine, oxazolidine, thiazolidine, imidazolidine,pyrazolidine, pyrrole, imidazole, pyrazole, 1,3,4-triazole,1,2,3-triazole, piperidine, morpholine, piperazine, and thiomorpholine,each being optionally substituted with one or more groups R_(a).
 24. Thecosmetic composition according to claim 23, wherein ring Q is aheterocycle selected from the group consisting of pyrrolidine,morpholine, and piperazine, each being optionally substituted with oneor more groups R_(a).
 25. The composition according to claim 24, whereinsaid compound has the structure I_(a).
 26. The composition according toclaim 25, wherein R_(a) is hydrogen, methyl, ethyl, propyl, and R₁ ishydrogen, methyl, ethyl, or propyl.
 27. The composition according toclaim 26, wherein R₄ to R₈ are independently hydrogen, methyl, ethyl,propyl, chloro, or bromo, with at least two of R₄ to R₈ being hydrogen.28. The composition according to claim 25, wherein the heterocycle ispyrrolidine.
 29. The composition according to claim 25, wherein theheterocycle is morpholine.
 30. The composition according to claim 25,wherein the heterocycle is piperazine.
 31. The method according to claim20, wherein the compound has the structure:

and wherein R^(b), R_(a), R₁, and Q are as set forth below: R^(b) R_(a)R₁

H

H

H

H


32. The method according to claim 20, wherein the compound has thestructure:

and wherein R^(b), R_(a), R₁, and Q are as set forth below: R^(b) R_(a)R₁

H

H


33. The cosmetic composition according to claim 20 wherein saideffective amount comprises from about 0.0001% to about 1% by weight ofthe total composition.
 34. The cosmetic composition according claim 33,wherein said effective amount is between about 0.001% to about 0.5% byweight of the total composition.
 35. The cosmetic composition accordingto claim 33, wherein said effective amount is between about 0.01% toabout 0.2% by weight of the total composition.